Rosuvastatin calcium, chemically known as bis[(E)[4-(4-fluorophenyl)isopropyl[methyl(methylsulfonyl)amino]pyrimidinyl](3R,5S)-3,5-dihydroxyhept enoic acid]calcium salt, is represented by the Formula I:

Fluvastatin sodium is known by its chemical name (±)7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy heptenoic acid monosodium salt. Fluvastatin sodium is a racemic mixture of the (3R,5S)- and the (3S,5R)-enantiomer and has the following Formula II:

Pitavastatin calcium is the common chemical name for bis[(E)-3,5-dihydroxy-7-[4′-(4″-fluorophenyl)-2′-cyclopropyl-quinolin-3′-hept-6-enoic acid]calcium salt, is represented by the Formula III:

Fluvastatin sodium, pitavastatin calcium and rosuvastatin calcium, hereinafter referred to as “the Agents”, are members of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. The Agents are potent inhibitors of the enzyme 3-hydroxy methylglutaryl-coenzyme Areductase (HMG CoA reductase) and are useful as pharmaceutical agents, for example in the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis, as well as other diseases or conditions in which HMG CoA reductase is implicated.
European Patent Application, Publication No. 521471 (hereinafter EP 0521471 B1), discloses an amorphous (powder) form of rosuvastatin calcium. International Patent Applications WO 00/49014 A1, WO 01/60804 A1 and WO 04/014872 A1 also disclose a non-crystalline form of rosuvastatin calcium. Both powder and non-crystalline rosuvastatin calcium described in these four references are hydrate amorphous forms of rosuvastatin calcium, which is prepared by dissolving the corresponding sodium salt in water, adding calcium chloride in water and collecting the resultant precipitate by filtration. The hydrate amorphous form is usually not very stable and thus often not ideal for the preparation of pharmaceutical composition. U.S. Pat. No. 6,589,959 B1, discloses a hydrate crystalline form (Form A) of rosuvastatin calcium and a method for its preparation.
Pitavastatin, its calcium salt (2:1) and its lactone are disclosed in three related U.S. patents (U.S. Pat. Nos. 5,011,930 A, 5,856,336 A and 5,872,130 A). In the 930' patent, pitavastatin sodium is prepared by converting ethyl (E)-3,5-dihodroxy[4′-(4″-fluorophenyl)-2′-(I cyclopropyl)-quinolin-3′-yl]-hept enoate, to the sodium salt in accordance to Example 2 by using an aqueous solution of sodium hydroxide. The compound is dissolved in ethanol, to which an aqueous solution of sodium hydroxide is added. The resulting mixture is stirred and the ethanol is removed under reduced pressure. Water is then added, and the mixture is further extracted with ether. The aqueous layer is then lyophilized to obtain the final product, or the aqueous layer is weakly acidified with a dilute solution of hydrochloric acid. The acidified aqueous layer is then extracted with ether. After extraction, the ether layer is dried over magnesium sulphate. Then the ether is removed under reduced pressure to obtain the sodium salt. The '930 patent and its related patents do not disclose the procedure for preparing the calcium salt of pitavastatin, and do not disclose amorphous or crystalline forms of pitavastatin calcium as well.
Fluvastatin as well as its sodium salt are disclosed in U.S. Pat. No. 4,739,073. In this patent, fluvastatin sodium is obtained by lyophilization. U.S. Pat. No. 6,124,340 A describes that lyophilization of fluvastatin sodium yields a mixture of a crystalline form (designated as Form A) and amorphous material. This patent further discloses a new crystalline form (designated as Form B) of fluvastatin sodium. The amorphous material obtained in these patents is not pure and contains about 50% crystalline forms. The estimated amount of form A obtained by lyophilization as described in these patents is about 50%. U.S. Pat. No. 6,696,479 B2 discloses additional four crystalline hydrates forms (Form C, D, E and F) of fluvastatin sodium.
The amorphous material of fluvastatin sodium obtained in these patents is also a hydrate, due to the use of a mixture of organic solvent and water as solvents. The hydrate amorphous form is often not very stable and not ideal for the preparation of pharmaceutical composition. An anhydrous amorphous form is often more stable and easier to purify than the corresponding hydrate amorphous form.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem Pharm Bull, 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favored over another. An amorphous form Cefuroxime axietil is good example for exhibiting higher bioavailability and the crystalline forms. Atorvastatin calcium, which is a member of the statin drugs, has been found that its crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body.
Therefore, there is a need to search new forms of rosuvastatin calcium, pitavastatin calcium and fluvastatin sodium.